Appending a tris-imidazole ligand with a Tyr244 mimic on the distal face of bromoacetamidoporphyrin

Article abstract of DOI:10.1021/ol049912m

(Equation presented) Bromoacetamidoporphyrin is a convenient synthon for the attachment of distal superstructures at room temperature in good yields. New models are presented that contain a tris-imidazole distal ligand set bound to the porphyrin in either a binary or trinary fashion. More importantly, one distal imidazole is cross-linked to a phenol mimicking Tyr²⁴⁴, making this model the closest structural analogue yet reported of the metal free cytochrome c oxidase (CcO) active site.

Full text of DOI:10.1021/ol049912m

ORGANIC
LETTERS
2004
Vol. 6, No. 6
1033-1036
Appending a Tris-imidazole Ligand with
a Tyr244 Mimic on the Distal Face of
Bromoacetamidoporphyrin
James P. Collman,* Richard A. Decre´au, and Simona Costanzo
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
jpc@stanford.edu
Received January 14, 2004
ABSTRACT
Bromoacetamidoporphyrin is a convenient synthon for the attachment of distal superstructures at room temperature in good yields. New
models are presented that contain a tris-imidazole distal ligand set bound to the porphyrin in either a binary or trinary fashion. More importantly,
one distal imidazole is cross-linked to a phenol mimicking Tyr244, making this model the closest structural analogue yet reported of the metal
free cytochrome c oxidase (CcO) active site.
Structural characterization of cytochrome c oxidase (CcO)
active sites1-2a-c has led to significant progress in the design
and synthesis of close structural CcO analogues. Several
linkers have been attached to amino-porphyrin 1 to perform
the tethering of the distal superstructure:3a-c Michael acceptor
porphyrins (2),3d-e chloroacetamidoporphyrins (3),3e-g and
isocyanatoporphyrins (4).3h Some, such as 4, are moisture-
sensitive or have been used with moisture-sensitive com-
pounds such as the acyl chloride superstructures in reaction
with 1. On the other hand, 2 and 3 are very stable in air, but
heating is required for them to react, which induces
significant rotation, lowering the yields and preventing
recovery of the unreacted starting material. A new deriva-
tization of porphyrin anilines is presented to obtain bro-
moacetamidoporphyrin synthon 5 offering a compromise
between reactivity and moisture sensitivity.
(3) (a) Collman, J. P.; Gagne, R. R.; Reed, C. A.; Halbert, T. R.; Lang,
G.; Robinson, W. T. J. Am. Chem. Soc. 1975, 97, 1427. (b) Collman, J. P.;
Broring, M.; Fu, L.; Rapta, M.; Schwenniger, R. J. Org. Chem. 1998, 63,
8084. (c) Collman, J. P.; Sunderland, C.; Boulatov, R. Inorg. Chem. 2002,
41, 2282. (d) Collman, J. P.; Zhang, X.; Herrmann, P. C.; Uffelman, E. S.;
Boitrel, B.; Straumanis, A.; Brauman, J. I. J. Am. Chem. Soc. 1994, 116,
2681. (e) Collman, J. P.; Boitrel, B.; Fu, L.; Galanter, J.; Straumanis, A.;
Rapta, M. J. Org. Chem. 1997, 62, 2308. (f) Collman, J. P.; Broring, M.;
Fu, L.; Rapta, M.; Schwenniger, R.; Straumanis, A. J. Org. Chem. 1998,
63, 8082. (g) Lindsey, J. S.; Prathapan, S.; Johnson, T. E.; Wagner, R. W.
Tetrahedron 1994, 50, 8941. (h) Collman, J. P.; Wang, Z.; Straumanis, A.
J. Org. Chem. 1998, 63, 2424.
(1) Ferguson-Miller, S.; Babcock, G. T. Chem. ReV. 1996, 96, 2889.
(2) (a)Iwata, S.; Ostermeier, C.; Ludwig, B.; Michel, H. S. Nature 1995,
376, 660. (b) Tsukihara, T.; Aoyama, H.; Yamashita, E.; Tomizaki, T.;
Yamaguchi, H.; ShinzawaItoh, K.; Nakashima, R.; Yaono, R.; Yoshikawa,
S. Science 1996, 272, 1136. (c) Tsukihara, T.; Aoyama, H.; Yamashita, E.;
Tomizaki, T.; Yamagushi, H.; Shinzawaitoh, K.; Nakashima, R.; Yaono,
R.; Yoshikawa, S. Science 1995, 269, 1069. (d) Yoshikawa, S.; Shinzawa-
Itoh, K.; Nakashima, R.; Yaono, R.; Yamashita, E.; Inoue, N.; Yao, M.;
Fei, M. J.; Libeu, C. P.; Mizushima, T.; Yamagushi, H.; Tomizaki, T.;
Tsukihara, T. Science 1998, 280, 1723.
10.1021/ol049912m CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/24/2004

Since the stability of the Cu complex in the tris-imidazole
pocket might be an issue,4 and tris-imidazolyl methane gives
stable complexes with copper(I) ions,5 Naruta et al.6a and
Collman et al.6b synthesized a new family of active-site
models with 6 and 7, in which a tris-imidazolyl moiety is
covalently linked to the porphyrin. However, this linkage to
the porphyrin was attached at only one position, which
allowed the triimidazole ligand to rotate. To obviate this
problem, a new family of cytochrome c oxidase models has
been developed (models 8-10). In models 8 and 9, the distal
tris-imidazole moiety and the proximal base are cross-trans-
linked to the RâRâ-porphyrin atropisomer in a binary fashion
reminiscent of previous porphyrin designs,7a-d whereas in
model 10, the former is linked in a trinary fashion to the
RRRâ-porphyrin. A phenol moiety that our previous models
lacked has been covalently linked to one distal imidazole in
model 8b. It mimics the Tyr244 residue, which is thought to
play a key role in the 4H+/4e- reduction of O28a-e and which
has been the subject of studies based on non-heme models.8f-j
Model 8b is a more representative model of the CcO active
site because all key groups are present: porphyrin, proximal
base, three distal imidazoles, and one imidazole linked to a
phenol residue. In model 9, an amine remains protected and
after deprotection may be used as a synthon for modifying
the superstructure.
Several synthetic routes were investigated for the prepara-
tion of the pyridine-diamine building block 16 (Scheme 1).
Following a previously reported procedure9a with some
modifications, 3,5-pyridine-dicarboxylic acid was converted
into the diacyl chloride 17, which was further reduced by
(4) Collman, J. P.; Boulatov, R.; Sunderland, C. J. In The Porphyrin
Handbook; Academic Press: Boston, 2003; Vol. 11, Chapter 63, pp 1-49.
(5) Sorrell, T. N.; Borovik, A. S. J. Am. Chem. Soc. 1987, 109, 4255.
(6) (a) Tani, F.; Matsumoto, Y.; Tachi, Y.; Sasaki, T.; Naruta, Y. Chem.
Commun. 1998, 1731. (b) Collman, J. P.; Zhong, M.; Wang, Z.; Rapta, M.
Org. Lett. 1999, 1, 2121.
(7) (a) Boitrel, B.; Lecas, A.; Renko, Z.; Rose, E. New J. Chem. 1989,
13, 73. (b) Momenteau, M.; Mispelter, J.; Loock, B.; Lhoste, J.-M. J. Chem.
Soc., Perkin Trans. 1 1985, 61. (c) Momenteau, M.; Mispelter, J.; Loock,
B.; Bisagni, E. J. Chem. Soc., Perkin Trans. 1 1983, 189. (d) Maillard, P.;
Schaeffer, C.; Huel, C.; Lhoste, J. M.; Momenteau, M. J. Chem. Soc., Perkin
Trans. 1 1988, 3285.
(8) (a) Gennis, R. B. Biophys. Biochim. Acta 1998, 1365, 241. (b)
MacMillan, F.; Kannt, A.; Behr, J.; Prisner, T.; Michel, H. Biochemistry
1999, 38, 9179. (c) Proshlyakov, D. A.; Pressler, M. A.; Babcock, G. T.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8020. (d) Proshlyakov, D. A.;
Pressler, M. A.; DeMaso, C.; Leykam, J. F.; DeWitt, D. L.; Babcock, G.
T. Science 2000, 290, 1588. (e) Sucheta, A.; Szundi, I.; Einarsdottir, O.
Biochemistry 1998, 37, 17905. (f) Collman, J. P.; Zhong, M.; Constanzo,
S.; Zhang, C. J. Org. Chem. 2001, 66, 8252. (g) Collman, J. P.; Wang, Z.;
Zhong, M.; Zeng, L. J. Chem. Soc., Perkin Trans. 1 2000, 8, 1217. (h)
Aki, M.; Ogura, T.; Naruta, Y.; Le, T. H.; Sato, T.; Kitagawa, T. J. Phys.
Chem. A 2002, 106, 3436. (i) Cappuccio, J. A.; Ayala, I.; Elliott, G. I.;
Szundi, I.; Lewis, J.; Konopelski, J. P.; Barry, B. A.; Einarsdottir, O. J.
Am. Chem. Soc. 2002, 124, 1750. (j) Kamaraj, K.; Kim, E.; Galliker, B.;
Zakharov, L. N.; Rheingold, A. L.; Zuberbuhler, A.; Karlin, K. D. J. Am.
Chem. Soc. 2003, 125, 6028.
lithium tri-tert-butoxyaluminum hydride to afford the dial-
dehyde 18 in 28% yield.9a To avoid the use of hydride in
the preparation of 18, 17 was converted into the pyridine-
bis-3,5(p-toluenesulfonylhydrazide) 19 in 82% yield.
This underwent a McFayden-Stevens reaction by treat-
ment with Na2CO3 to afford 18 in 25% yield. A simpler
approach employed a Riley oxidation of 3,5-dimethyl pyri-
dine yielding 18 in 20% yield. Pyridine dicarbinol 20 was
oxidized to 18 in 32% yield by treatment with MnO2. LiAlH4
reduction of pyridine diester 21a,b led to 20 in poor yields,
contrary to previous reports.9b-e,7c However, the polymer-
supported borohydride reduction of 17, previously reported
by Ley for the reduction of pyridine acyl chloride species,9d
(9) (a) Choma, C. T.; Kaeslte, K.; Akerfeldt, K. S.; Kim, R. M.; Groves,
J. T.; DeGrado, W. F. Tetrahedron Lett. 1994, 35, 6191. (b) Queguiner,
G.; Pastour, P. Bull. Soc. Chim. Fr. 1968, 4117. (c) Palecek, J.; Ptackova,
L.; Kuthan, J. Coll. Czechosl. Chem. Commun. 1969, 34, 427. (d)
Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1999,
1253.
1034
Org. Lett., Vol. 6, No. 6, 2004

Scheme 1a
Scheme 2a
a Reagents and conditions: (a) SOCl2, DMF cat., toluene, 110
°C, 95%; (b) (t-BuO)3AlH, THF, -78 f 0 °C, 28%; (c) TsNHNH2,
CH2Cl2/C6H5N, 40 °C, 82%; (d) SeO2, dioxane-water, 80 °C, 12
h, 20%; (e) polymer-N+Me3BH4-, CH2Cl2, 0 °C, 30 min, 43%;
(f) MnO2, CH2Cl2, rt, 2 h, 32%; (g) K2CO3, glycol, 150 °C, 5 min,
25%; (h) LiAlH4, THF, -78 f 0 °C, 5-10%; (i) CH3NH2, CH3OH,
rt, 16 h, 50%; (j) NaBH4, CH3OH, 10 min, 50%; (k) ROH, H2SO4,
80 °C, 3 h, 80%.
a Reagents and conditions: (a) bromoacetyl bromide, THF,
Et2NC6H4, 0 °C, 2 min, 86%; (b) chloroacetyl chloride, CH2Cl2,
15 min, rt, 80%; (c) 16, THF, Et2NC6H4, rt, 36 h (45% (26a)) or
4 weeks (14% (26b)), or 60 °C (25% (26b)); (d) THF, Et2NC6H4,
rt, 36 h, 22 (40% (8)) or 23 (35% (9)); (e) NaI, acetone, 50 °C, 16
h, then step d, 8%; (f) BBr3, CH2Cl2, -78 °C, 30 min, then 0 °C,
1 h, 40%.
yielded 20 in 43% yield. Diimination of 18 by treatment in
methylamine followed by reduction with NaBH4 afforded
the desired diamine pyridine 16 in 65% yield.
Preparation of RâRâ-models 8 and 9 was achieved by SN2
reaction of bis-secondary amine straps 16, 22, and 23 with
a tetrahalogenoacetamidoporphyrin 24a,b (Scheme 2). The
sequence was chosen to introduce the pyridine tail 16 first,
followed by the tris-imidazole ligand 22 or 23 because the
purification of imidazole-containing porphyrins is always
tedious. The previously reported chloroacetamidoporphyrin
TClPP 3 3e,f required halogen exchange and heating (45-60
°C) for 18-72 h to be condensed with secondary amines in
ca. 40% yield.3c But a control reaction showed that RâRâ-
TClPP 25b refluxed in acetone (55 °C) for 6 h led to 50%
rotation. Therefore, the preparation of bromoacetamido-type
porphyrins 24a,c,e was carried out since Br is a better leaving
group for SN2 reactions and should allow milder reactions.
Tetra(bromoacetamido)-porphyrin 24a (RâRâ-TBrPP) is
obtained in 86% yield by addition of bromoacetyl bromide
to RâRâ-tetraaminophenyl-porphyrin synthon 25a. A short
reaction time and low temperature are required; otherwise,
side-products form. Preparation from a pure TAPP-atropi-
somer was preferred over a mixture of TAPP-atropisomer
because separation of TBrPP-atropisomers have closer Rf
values than TAPP, making them more difficult to separate.
Subsequent reaction of 24a and diamine 16 proceeded at
room temperature, affording 26 in 45% yield, with no
observed rotation. The same reaction run with TClPP 24b
led to 14% of 26b after a reaction time of several weeks at
room temperature and 23% yield when the reaction was
carried out at 50 °C. The subsequent reaction of 26a with
tris-imidazole dipodal ligands 228c and 23 proceeded at room
temperature and led to 8 and 9 in 40 and 35% yields,
respectively. Longer reaction times led to a drop in yield of
8 and 9 together with other unidentified fractions, presumably
arising from SN2 nucleophilic attack of the unprotected
imidazolic nitrogen on the bromomethylene of unreacted 24a
as pointed out earlier with imidazol acyl chlorides.3b
As expected, a gain in reactivity is obtained with TBrPP.
Reaction times were slightly shorter than with TClPP, but
no heating was required, which allowed recovery of the
starting porphyrin; also, the yields of products were slightly
increased. TBrPP is not as moisture sensitive as the very
reactive isocyanatoporphyrin 4: this strategy represents a
compromise between sufficient reactivity and convenience
of handling. Unreacted 24a did not suffer from rotation or
hydrolysis during the reaction and workup, which is normally
an issue when dealing with valuable porphyrin synthons such
as 26a in the synthesis of 8a or 9. TBrPP 24a is stable when
stored at 4 °C, whereas dibromoacetamidopyridine-strapped
porphyrin 26a was slowly converted into several unidentified
porphyrins of higher polarity. Similarly, the preparation of
R3[bromoacetamido]-â -[trityl]-porphyrinR3BrâTr24c(Scheme
3) from R3[amino]-â -[trityl]-porphyrin 25b3f was achieved
in 55% yield. A 40-fold excess of base was required to keep
trityl cleavage to a minimum. R3BrâTr Synthon 24c was
stable at room temperature in solution for hours. Reaction
of tripodal ligand tris-imidazole-tris-secondary amine 278f
with 24c led to RRRâ-model 10 in 28% yield together with
several unidentified side products. When starting from 24d,
prior halogen exchange was required and the isolated yield
of 10 was only 6.5%.
Previously reported condensations were also run with the
new bromoacetamido linker. Tris-imidazole-picket-â-trityl-
Org. Lett., Vol. 6, No. 6, 2004
1035

spectroscopic characteristics: lower solubility in common
organic solvents, smaller Rf values, and halogeno-methylene
1H NMR signals downfield-shifted (by 0.24 ppm) with
bromine. 8a has theoretically several isomers: the phenoxy-
imidazole moiety can rotate along the C-N axis giving two
possible isomers, one with the moiety up, the other with the
moiety down. The phenoxy moiety can also rotate along the
C(imidazole)-C(phenyl) bond: two extreme positions might
be considered, inside (in) or outside (out) together with other
intermediate positions. This is another kind of rotational
isomer taking place on porphyrin at the superstructure and
not at the meso-phenyl rings.
Scheme 3a
Scheme 4
a Reagents and conditions: (a) bromoacetyl bromide, THF,
Et2NC6H4, 0 °C, 2 min, 86%; (b) chloroacetyl chloride, CH2Cl2,
15 min, rt, 70%; (c) 27, THF, Et2NC6H4, rt, 36 h, 28%; (d) NaI,
acetone, 50 °C, 16 h, then step c, 6.5%.
porphyrin 113f was obtained in 40% yields by reaction of
24c with cyanoethyl-protected imidazole3f followed by
treatment with sodium methylate. Capping of R3- and R4-
porphyrins R3BrâTr 24c and RRRR-TBrPP 24e with triaza-
cyclononane and cyclen led to porphyrins 12 and 13 in 43-
50% yield.
Interconversion was slow enough at room temperature to
attempt chromatographic separation, but because of the
similar polarity of the atropisomers, only one atropisomer
could be purified. As for the other fractions, the same peak
1
at m/z 1464.5 was found, and broad H NMR peaks were
obtained. Interconversion was much faster above 30-40 °C,
which is reminiscent of the rotation of meso-amino pickets
previously reported,3a which did not allow the use of high-
temperature NMR with 8a,b. With the more polar compound
8b, obtained by BBr3 treatment of 8a, isomers were not even
detected on TLC.
In conclusion, a new generation of models is reported
where capped and strapped tris-imidazole porphyrins offer
greater stability and no rotation of distal Cu complexes. One
of them is the closest structural analogue yet reported of the
metal free CcO. The bromoacetamido linker is efficient in
attaching a variety of distal tris-imidazole superstructures.
It offers a compromise between high reactivity and conven-
ience in handling.
Also, mono- and bis-strapped R4-porphyrins 14 and 15,
respectively, were obtained by reaction of 24e with dimeth-
ylethylenediamine. Contrary to 24c and 26a, 15 is less stable
in solution, as unidentified polar fractions appeared after
several hours, presumably from nucleophilic attack of the
poorly hindered tertiary amine on the bromomethylene
picket. Also, in capped and strapped porphyrins 12-15, there
is only one methylene per acetamido picket in contrast to
previously capped and strapped porphyrins, where two
methylenes per acetamido picket are present.3d-f This is an
issue when considering Fe/Cu distances in the metalated
models.
Acknowledgment. This material is based upon work
supported by the National Institutes of Health under Grant
No. 017880. Support from NSF Grant CHE-013206 also
contributed to this work. Dr. Chi Zhang is acknowledged
for preparing some 16 from 18, and Dr. Minh Zhong for
providing p-toluenesulfinic acid. R.A.D. thanks the French
Foreign Ministry for a LaVoisier fellowship. We also thank
the Mass Spectrometry Facility, University of California, San
Francisco, and the Stanford University Mass Spectrometry.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds 8-10,
12, 14-16, 19, 23-24, and 26a,b. This material is available
free of charge via the Internet at http://pubs.acs.org.
The tris-imidazole strapped and capped models 8-10 are
more polar than tris-imidazole picket porphyrins. With
respect to chloroacetamido-type porphyrins, the new bro-
moacetamidoporphyrins display the following physical and
OL049912M
1036
Org. Lett., Vol. 6, No. 6, 2004